literatura hispana
4. La Abjuración El silencio de sor Juana
Identifi cation of Women at Risk of Primary T gondii Infection During Pregnancy
In a study by Boyer et al, 24 only 48%
of mothers of infants with CT had clinical symptoms suggestive of acute toxoplasmosis during pregnancy or had reported risk factors for T gondii exposure (eg, exposure to undercooked meat or to cat feces). Only routine serologic screening during pregnancy would have identified the rest of the women, who were nevertheless at risk of delivering infected infants.
In addition, only 49% of mothers of infants with CT who had serologically documented evidence of acute T gondii infection acquired from oocysts had also reported that they had significant risk factors for such exposures. 23 (Of note,
laboratory tests to detect antibodies to sporozoite-specific antigens are performed only in research laboratories. 54)
Antepartum Maternal Screening and Neonatal Screening Programs Among Western European countries, only France 2 and Austria 211 have
implemented long-standing free national routine antepartum screening programs (monthly screening until the end of pregnancy in France since 1978 111 and once per
trimester in Austria since 1975, 212, 213
although shorter intervals [maximum every 8 weeks] were later advocated by experts). Screening once per trimester leaves a “blind period” during maternal infections late in pregnancy. 214
Their approach was followed by other countries, including Italy and Slovenia. In 1998, Italy passed legislation that requires screening for toxoplasmosis of all pregnant women. This program was implemented mostly in the northern parts of Italy, and according to the latest Italian recommendations, screening should
begin by 13 weeks of gestation and continue monthly until the end of pregnancy. 215 In Switzerland,
screening was applied only regionally in the Basel region and only for surveillance purposes. 212, 216 In
many other European countries, antepartum screening was widely adopted by experts and physicians despite the absence of national mandatory antepartum screening programs; this phenomenon has been termed “wild screening.” 212
Neither France nor Austria complemented their antepartum screening programs with additional postnatal surveillance programs for CT for approximately 3 decades. A recent European survey of 28 European countries in 2007 identified only 4 countries that had surveillance screening programs specifically for CT (France, Germany, Italy, and Denmark). 9 Twelve
other countries had surveillance systems only for symptomatic toxoplasmosis (CT or noncongenital toxoplasmosis), and another 12 did not have any surveillance systems for toxoplasmosis. The neonatal screening program for CT in France started only in 2007. In Italy, neonatal screening for CT is only regionally applied to the Campania region (since 1997). Denmark 114
had a national neonatal screening program since 1997, but this program was discontinued in August of 2007 because it was thought that there was no benefit from postnatal treatment, because some infants with CT developed new eye lesions despite postnatal treatment (3 new eye lesions developed during a 3-year follow-up period among 32 infants evaluated 217). However,
children with CT in this program were treated for a very short period of time (3 months) as opposed to the longer 12-month postnatal treatment courses proposed in other European countries (Table 11). In 2007, a dedicated surveillance network for CT also was instituted in Greece. 218
Cost-effectiveness of Antepartum and Postnatal Screening Programs for Toxoplasmosis in the United States
The preventive effect of
toxoplasmosis screening of pregnant women depends on both the magnitude of disease caused by CT (the incidence of maternal infection during pregnancy multiplied by the risk of MTCT multiplied by the proportion of symptomatic infected children) and the preventable proportion of disease (the sensitivity of the screening strategy multiplied by the efficacy of the preventive treatment multiplied by the adherence to therapy). Early studies evaluating the cost-effectiveness of antepartum toxoplasmosis screening programs yielded conflicting results. 7, 219 The
1999 study by Mittendorf et al 219
concluded that antepartum screening was not cost-effective, whereas the most recent 2011 decision analysis by Stillwaggon et al 7 concluded that
implementation in the United States of a universal monthly screening of pregnant women, following the French protocol, is cost-effective and leads to a savings of $620 per screened infant if the incidence of CT in the United States is greater than 1 per 10 000 live births. This decision analysis made a number of assumptions, including a cost of $12 per test, an estimated cost of fetal death of over $6 million, and an incidence of acute primary maternal infection during pregnancy of 1 in 1000 (including also sensitivity analysis for an incidence of acute maternal infections as low as 0.2 cases/1000 pregnant women). It also assumed that treatment was highly efficacious and inexpensive. Although the study concluded that screening in the United States would be cost-effective, it remains unclear whether these conclusions would be reached if data were used assuming higher costs of screening, lower costs of loss, and less efficacy of treatment.
Previous decision analyses have not arrived at the same conclusions.8
However, in this previous decision analysis, among the strategies analyzed was pregnancy termination for documented fetal infections. The early Cochrane systematic review on treatments for toxoplasmosis during pregnancy published in 2000 suggested that, in countries where screening or treatment is not routine, these technologies should not be introduced outside the context of a carefully controlled trial. 5
Several assumptions made in the earlier decision analysis by Mittendorf et al 219 differ from current
evidence. Mittendorf et al 219 assumed
that antepartum screening tests had a very low specificity, which translated to a very low PPV for a relatively rare disease like CT. This assumption was incorrect for samples sent for further confirmatory testing at the PAMF-TSL, 162 because confirmatory
testing at the PAMF-TSL has been shown to have a specificity of 100% for the differentiation of acute from chronic T gondii infections. 160, 220, 221
The diagnostic tests used at the PAMF-TSL have been extensively cross-validated against national reference laboratories in France by using sera from pregnant women with complete ascertainment of their T gondii infection status. Furthermore, AF PCR assay has a specificity and a PPV of nearly 100%, 112, 170 which means that
a positive AF PCR assay result is diagnostic of fetal infection. In addition, in the Mittendorf et al study, pregnancy termination rates were assumed to be very high (they assumed that 12.1 fetuses without CT would be aborted for every fetus truly diagnosed with CT). 219 According
to recent evidence, pregnancy termination would not be routinely performed once the diagnosis of CT is made.131 Confirmatory serologic
testing in a reference laboratory and communication and interpretation of the results by an expert decreased
the rate of unnecessary abortions by approximately 50%. 167 AF PCR
assay and fetal ultrasonography to confirm or exclude fetal infection and symptomatic CT may further decrease the number of elective abortions. Further support against pregnancy terminations for CT is provided by the analysis of Berrebi et al 131; even among fetuses infected
in the first trimester and with normal fetal ultrasonograms, 97% (35 of 36) would be either completely asymptomatic (78% [28 of 36]) or only slightly affected at birth (19% [7 of 36] had chorioretinitis and/ or moderate ventricular dilatation). Of note, all of these fetuses had mothers who received antepartum treatment. The updated review of the French experience over the past 2 decades (1987–2008) described a fetal loss rate of 0.9% (N = 18) and a pregnancy termination rate of 1% (N = 21). 2 Moreover, in the SYROCOT
international consortium of CT, the reported fetal death rate was similar (∼2%; 22 terminations of pregnancy [1%] and 13 fetal deaths [0.7%] among the 1745 pregnant women with primary T gondii infections from the 26 international cohorts). 1
In the more recent 2011 Stillwaggon et al 7 study, universal antepartum
screening in the United States following the French protocol of monthly serologic screening during pregnancy (started at 11 weeks of gestation), antepartum treatment, fetal ultrasonography/AF PCR assay, and postnatal serologic and clinical follow-up of infants and treatment of infants as indicated was cost-saving. The findings from this analysis were robust to changes in the incidence of acute maternal primary infections, value of life, and test costs. Specifically, the screening approach included initial screening with commercial tests for IgG and IgM (at a cost of $12 per test) and subsequent confirmatory testing in reference laboratories of any
positive results by using a panel of tests with high diagnostic accuracy and a specificity of 100% 161 (at a
cost of $385 per confirmatory panel of tests). The cost of $12 per test included the costs for phlebotomy and reagents in a community
hospital. Universal screening strategy remained a cost-saving approach, even for an incidence of maternal primary infections as low as 0.2 acute infections per 1000 women. This incidence would translate to approximately 0.5 CT cases per 10 000 children if a 25% MTCT risk is assumed. Moreover, the estimated cost of $12 per test is also in the cost range of several recently developed (already commercially available) tests for toxoplasmosis with novel technologies.
According to Calderaro et al, 160 who
validated the diagnostic performance of 4 commercially available IgG and IgM tests for toxoplasmosis, there are commercially available IgG and IgM tests that have 100% analytical sensitivity and specificity. Moreover, according to the Wilson et al 161
validation published in 1997, of 6 commercial IgM tests, there are commercially available IgM tests with a specificity up to 98.6% (eg, the Vidas-Biomerieux IgM). In more detail, Calderaro et al showed that the sensitivity (point estimate) of all 4 commercial IgG assays tested was 100% and the specificity (point estimates) of the different IgG tests ranged between 98.5% and 100%. In the same study, the sensitivity (point estimates) of 4 commercial IgM tests ranged between 82.4% and 100% and the specificity ranged between 99.7% and 100%. Moreover, according to Wilson et al, 161 in an
FDA-sponsored validation study of 6 commercial IgM tests, the sensitivity (point estimates) of these 6 IgM tests ranged from 93.3% to 100% and the specificity (point estimates) ranged from 77.5% to 98.6%. In reference laboratories, the specificity of confirmatory testing (for the
diagnosis of a recently acquired acute infection) is 100%. 161
Assumptions used in the decision analysis by Stillwaggon et al 7 were as
follows:
1. a rate of acute maternal primary infections during pregnancy of 1.1 in 1000 (this is likely an overestimate, because it was based on US data from 1959– 1966 and might not represent the incidence of acute T gondii infection during pregnancy in the current era with the decreasing overall seroprevalence rates; however, sensitivity analyses in this article revealed that the screening strategy would remain cost saving even at a rate of acute maternal infections as low as 0.2 per 1000 women);
2. a probability of fetal infection after acute maternal primary infection of 50% 96, 222 –226;
3. a probability of fetal death attributable to CT of 5%; 4. an estimated cost for fetal death
attributable to CT of $6 million; 5. a probability of visual impairment
from undiagnosed CT and no antepartum treatment of 48%; 6. a probability of visual and
cognitive impairment of 45%; and 7. varying probabilities of visual
impairment and visual/cognitive impairment for fetal infections by trimester.
These high rates of unfavorable outcomes from CT used in their model come from the older literature of infants with CT whose mothers were not treated during pregnancy. 7, 96, 131, 222 –226
A study limitation that was acknowledged by Stillwaggon et al 7 was that this decision analysis
model assumed that all mothers in the United States would receive care by 12 weeks of gestation and would adhere to monthly follow-ups. However, this assumption might
not represent a reality in the United States. Experience from France and Austria, where antepartum screening has been conducted for many years, indicated that late initial testing was common (25% of French pregnant women had their first test performed late) and there was also poor adherence to screening (only 30%–40% of pregnant women in France and Austria had all their mandatory antepartum screening tests completed). 95, 212, 214 It remains
unclear how much a low adherence rate in pregnant women in the United States will affect the conclusions of this decision analysis. A follow-up decision analysis study should try to explore how changes in adherence rates with regard to the time of initiation of screening and the frequency of screening will affect the conclusions of this analysis.
Low-cost tests in state laboratories, combining screening for
toxoplasmosis with screening for other congenital infections, may further reduce the screening cost (test cost and shipping cost) while keeping a centralized quality control for those screening tests (in the state laboratories) and maintaining high-quality confirmatory testing (at reference laboratories). Moreover, novel technologies are already widely used by several companies around the globe that provide low-cost serologic tests (eg, using microfluidics technologies in lateral flow devices, the recently introduced plasmonic gold technology). 227 Some
of these technologies are already commercially available in the United States. Of course, previous rigorous validation of these novel tests is required to better understand their role in universal screening programs.
Moreover, the following changes in the future may make the universal screening strategy even more cost- effective: (1) “point-of-care test” technologies for serologic screening, (2) screening with the use of saliva
specimens, and (3) multiplex screening 227 (multiplex IgG/IgM,
which already are under evaluation and will soon provide further cost- saving alternatives for screening). In addition, screening for >1 congenital disease at the same time will provide further cost savings. Assessments of the feasibility of any universal antepartum screening strategy should take into account several strict criteria that should be fulfilled before any such strategy is considered feasible but should also take into account the rapidly changing picture in the field of novel diagnostic technologies.
In summary, the decision analysis article by Stillwaggon et al 7
indicated that prenatal screening and treatment of toxoplasmosis in the United States could be a cost- saving approach for congenital toxoplasmosis but only under the assumptions included in the model. Although several sensitivity analyses in their model (including variations for the main assumptions such as incidence of acute
maternal infections, cost of tests and life-value equivalent) showed that the results were robust, the implementation of such a screening program would, nevertheless, require a significant reduction in the current cost of screening laboratory tests and significant changes in the structure of the US prenatal care system.
Aside from universal antepartum screening for toxoplasmosis, additional approaches to consider include the following: (1) antepartum education of women to avoid T gondii–related exposures during pregnancy and (2) ascertainment of adherence to antepartum screening, at least in high-risk women (eg, those with reported exposures through the oral route [oocyst/sporozoite-related exposures to cat feces and/or tissue cysts/bradyzoite-related exposures via ingestion of undercooked meat];
occupational exposures; immigrants from high-incidence areas;
women traveling internationally during pregnancy; women with immunosuppressive diseases). However, physicians should be aware that selective screening of pregnant women on the basis of self-reported exposure risk factors has the potential to miss more than approximately 50% of women who give birth to infants with CT and thus probably a much larger
number of acutely infected pregnant women.
If adherence to antepartum screening is poor, neonatal screening programs can at least capture infants with CT who were not detected in utero who would benefit from postnatal treatment. Nevertheless, the risk of adverse long-term sequelae in children in the United States who were only postnatally treated (and whose mothers did not receive antepartum treatment) is significant (85% with vision impairment, 36% with recurrences in eye disease, 27% with abnormal cognition at or after 3.5 years of age, and 16% with a decrease in IQ of >15 points). 110
Primary Prevention Strategies Primary prevention strategies in seronegative individuals are shown in Table 13. A survey of pregnant women in the United States
indicated that the majority were not aware that acquisition of
T gondii infection was associated with the consumption of
undercooked meat. 228
Effect of Antepartum Education on the Prevention of CT
The efficacy of preventive educational interventions targeting pregnant women has been studied by 2 cluster- randomized controlled trials with a total of 5455 women, 229 but both
of them were of low methodologic quality and did not target any objective clinical outcomes. Studies in Belgium from 1979–1982 and 1983– 1990 in which antepartum education started around the tenth week of pregnancy, and therefore could not significantly affect transmission rates in the first trimester, have shown that educational tools targeting pregnant women reduced seroconversion rates by 63% to 92%. 230 However, other
epidemiologic studies, summarized
in the systematic review by Gollub et al, 12 failed to replicate those
findings.
A survey in 2006 of a random sample of 1200 US obstetrician/ gynecologists revealed that although all respondents routinely counseled their pregnant women about risks associated with handling cat litter, fewer had counseled them about risks associated with eating undercooked meat (78%), handling raw meat (67%), gardening (65%), or the need to wash fruit and vegetables (34%). Of note, 73% of the respondents were not aware that Toxoplasma IgM tests from nonreference laboratories could have a high false-positive rate, and most (91%) were not aware of the Toxoplasma
IgG-avidity test that could be used to determine the most likely time at which T gondii infection was acquired during pregnancy. The identified educational
knowledge gaps were subsequently addressed in a practice bulletin from the American College of Obstetricians and Gynecologists. In 2012, an updated survey was TABLE 13 Measures for Primary Prevention of T gondii Infection in Seronegative Pregnant Women, According to the PAMF-TSL Experience and CDC Recommendations61
Transmission Recommendations/Considerations
Meat and other edibles • Meat should be cooked up to at least 63°C (145°F) for whole cut meat (excluding poultry), up to at least 71°C (160°F) for ground meat (excluding poultry), and up to at least 74°C (165°F) for all poultry (whole cuts and ground) (a food thermometer should be used)
• Meat should be frozen at –20°C (–4°F) for at least 48 hours
• Freezing and thawing at specifi c temperatures for specifi c time can kill T gondii tissue cysts • Infected meat that has been smoked, cured in brine, or dried may still be infectious • Contact with mucous membranes should be avoided when handling raw meat
• Gloves should be worn when handling raw meat and hands should be thoroughly washed after handling raw meat • Kitchen surfaces and utensils should be thoroughly washed after contact with raw meat
• Drinking unpasteurized goat milk should be avoided • Eating raw oysters, clams, or mussels should be avoided • Skinning or butchering animals without gloves should be avoided
Untreated water • Drinking untreated water, including that from wells, or water with potential contamination by feces from domestic or wild cats should be avoided
Cat feces and soil • Contact with material/soil potentially contaminated with cat feces, especially handling of cat litters or gardening, should be avoided. However, if not possible to be avoided, disposable gloves should be worn when gardening and during any contact with soil or sand and hands should be washed with soap and warm water afterward.
• Cats should be kept indoors. Stray cats should not be handled or adopted while the woman is pregnant.
• Cat litter box should be changed daily, because T gondii does not become infectious until 1 to 5 days after it is shed in a cat’s feces. • Cats should be fed canned or dried commercial food, not raw or undercooked meats.